Explore the mechanism of LKRSDH metabolic function regulation on circadian rhythm during the aging process [ChIP-seq]

Although amino acid metabolism and epigenetic modifications are known to independently influence rhythmic decay, the mechanisms integrating these processes remain elusive. Here, we identify the bifunctional enzyme LKRSDH as a critical regulator of age-related circadian rhythms, operating through a dual role in metabolic catalysis and epigenetic modulation.

Integrating metabolomic and transcriptomic profiling, we demonstrate a functional link between LKRSDH and branched-chain amino acid metabolism. Specifically, we find that dietary isoleucine supplementation rescues age-related rhythmic decay and extends lifespan in LKRSDH mutants. Mechanistically, isoleucine modulates the genomic distribution of LKRSDH-mediated H3R17me2 and H3K27me3 modifications, which in turn regulates the transcription of insulin-like peptides, the downstream effectors of longevity and rhythmic stability.